This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inositol 1,4,5-trisphosphate receptors (IP3Rs) are the intracellular Ca2+ release channels gated by inositol 1,4,5-trisphosphate (IP3). These channels allow rapid fluxes of Ca2+ ions from the endoplasmic reticulum, thereby playing a key role in neurotransmitter release, fertilization, hormone secretion, gene transcription, metabolic regulation and apoptosis. In mammals, 3 different IP3R genes, sharing ~70% homology, are expressed. Individual cell types can express more than one isoform, and they may form homo- or hetero-tetrameric populations. The type 1 IP3R (IP3R1) is the predominant type in the cerebellar endoplasmic reticulum (ER), forming homo-tetramers with a Mr over 1.2 MDa. The cerebellum is generally used as a primary source for purification of the IP3R1 for structure-function characterization. The long-term objectives of this project are to determine the molecular mechanisms of the IP3-induced Ca2+-gating through structure-function analysis of the IP3R channel complex and to define how defects in this channel protein can cause abnormal regulation of cell Ca2+ level underlying human diseases such as cardiac hypertrophy, heart failure, hereditary ataxias, osteoporosis, atherosclerosis and some migraines.